17-02-2013, 07:59
I think this page in the article sums up what people are trying to achieve in NBE and may help you understand why programs have the components they have.
"The majority of mammary gland development occurs postnatally and involves the influence of
both local and circulating hormones and growth factors. However, full differentiation requires
pregnancy, and therefore PRL, as addressed earlier in this introduction. For normal development,
ovarian hormones such as estrogen and progesterone are important in control of ductal outgrowth
and alveolar expansion. This is through the regulation of cell proliferation, cell turnover and
differentiation in normal epithelium though paracrine mediators including EGF-related, IGF,
FGF, and TGF-β families during the estrous cycle (270-272).
Mammary gland development and differentiation are regulated by complex interactions
involving the hormones estrogen, progesterone, prolactin as well as insulin and glucocorticoids
(273). Like PRL, most of what is known about the role played by estrogen and progesterone in
mammary gland development has come from transgenic mouse models. Estrogen exerts its
activity by binding to the estrogen receptor (ER) which exists as two isoforms, ERα and ERβ.
While ERα is required for both normal ductal formation and outgrowth, deletion of ERβ has no
effect on ductal and alveolar development. However, ERα is not important in alveolar expansion
during pregnancy (274;275).
Progesterone, like estrogen, is also important in mammary gland development and acts
through the progesterone receptor (PR) which exists also in two isoforms, PR-A and PR-B. The
synthesis of PR in the mammary gland is regulated by estrogen and progesterone can antagonize
estrogen action by downregulating its own receptor (276). Additional studies indicate that PR
expression is associated with ERα and ERβ status (277). In juvenile mice, PR is evenly
expressed in the ductal epithelial but becomes more concentrated in certain regions in mature
virgin mice (278). During pregnancy, PR is expressed in cells associated with adjacent
proliferating cells. Experiments have indicated that progesterone signals the proliferation of
neighbouring cells during pregnancy but is also localized to the proliferative end buds of the
pubertal mouse mammary gland (279). Progesterone receptor knockout mice show subdued
alveolar development in the absence of both isoforms or only PR-B (280-282), while PR-A KO
has no effect on development (283).
In addition to estrogen and progesterone, growth hormone also plays a role in mammary
development but to a lesser extent. While PRL is critical for the development of lobuloalveolar
structures during pregnancy, growth hormone receptor (GHR) is not necessary for alveolar
development. However GH promotes ductal outgrowth and side-branching, which is suppressed
in GHR -/- transgenic mice. Because ductal outgrowth and side-branching are recovered when
null tissue is transplanted into wildtype mice, GH may be acting through stromal targets during
mammary development (128). GH overexpression has been shown to induce over-stimulation of
mammary glands and enhanced tumor development in mice (284).
Finally, glucocorticoids (GC) have also been shown to regulate epithelial cell proliferation
(285) as well as cell apoptosis in the mammary (286). Activation of the glucocorticoid receptor
(GR) enhances Stat5 signaling in the mammary gland (287) and has been shown to alter milk
production (288). While progesterone inhibits PRL activation of casein genes, GCs amplify its
action on transcription (289).
"The majority of mammary gland development occurs postnatally and involves the influence of
both local and circulating hormones and growth factors. However, full differentiation requires
pregnancy, and therefore PRL, as addressed earlier in this introduction. For normal development,
ovarian hormones such as estrogen and progesterone are important in control of ductal outgrowth
and alveolar expansion. This is through the regulation of cell proliferation, cell turnover and
differentiation in normal epithelium though paracrine mediators including EGF-related, IGF,
FGF, and TGF-β families during the estrous cycle (270-272).
Mammary gland development and differentiation are regulated by complex interactions
involving the hormones estrogen, progesterone, prolactin as well as insulin and glucocorticoids
(273). Like PRL, most of what is known about the role played by estrogen and progesterone in
mammary gland development has come from transgenic mouse models. Estrogen exerts its
activity by binding to the estrogen receptor (ER) which exists as two isoforms, ERα and ERβ.
While ERα is required for both normal ductal formation and outgrowth, deletion of ERβ has no
effect on ductal and alveolar development. However, ERα is not important in alveolar expansion
during pregnancy (274;275).
Progesterone, like estrogen, is also important in mammary gland development and acts
through the progesterone receptor (PR) which exists also in two isoforms, PR-A and PR-B. The
synthesis of PR in the mammary gland is regulated by estrogen and progesterone can antagonize
estrogen action by downregulating its own receptor (276). Additional studies indicate that PR
expression is associated with ERα and ERβ status (277). In juvenile mice, PR is evenly
expressed in the ductal epithelial but becomes more concentrated in certain regions in mature
virgin mice (278). During pregnancy, PR is expressed in cells associated with adjacent
proliferating cells. Experiments have indicated that progesterone signals the proliferation of
neighbouring cells during pregnancy but is also localized to the proliferative end buds of the
pubertal mouse mammary gland (279). Progesterone receptor knockout mice show subdued
alveolar development in the absence of both isoforms or only PR-B (280-282), while PR-A KO
has no effect on development (283).
In addition to estrogen and progesterone, growth hormone also plays a role in mammary
development but to a lesser extent. While PRL is critical for the development of lobuloalveolar
structures during pregnancy, growth hormone receptor (GHR) is not necessary for alveolar
development. However GH promotes ductal outgrowth and side-branching, which is suppressed
in GHR -/- transgenic mice. Because ductal outgrowth and side-branching are recovered when
null tissue is transplanted into wildtype mice, GH may be acting through stromal targets during
mammary development (128). GH overexpression has been shown to induce over-stimulation of
mammary glands and enhanced tumor development in mice (284).
Finally, glucocorticoids (GC) have also been shown to regulate epithelial cell proliferation
(285) as well as cell apoptosis in the mammary (286). Activation of the glucocorticoid receptor
(GR) enhances Stat5 signaling in the mammary gland (287) and has been shown to alter milk
production (288). While progesterone inhibits PRL activation of casein genes, GCs amplify its
action on transcription (289).