南方科技大学知识苑(SUSTech KC): MOLECULAR MECHANISM OF MAMMARY GLAND DEVELOPMENT AND BREAST CANCER PROGRESSION

题名	MOLECULAR MECHANISM OF MAMMARY GLAND DEVELOPMENT AND BREAST CANCER PROGRESSION
姓名	马路遥
姓名拼音	MA Luyao
学号	11850021
学位类型	博士
学位专业	生物学
导师	孙颖
导师单位	生物系
论文答辩日期	2022-11-22
论文提交日期	2022-12-21
学位授予单位	香港大学
学位授予地点	香港
摘要	The mammary gland is a mammal-specific organ, playing an important role in feeding and reproduction. However, the exact mechanism of mammary gland development is not completely understood. In this project, I first studied a new signaling pathway that may regulate mammary gland development. I focused on planar cell polarity (PCP) signaling, which is critical for embryonic development and organogenesis. As PCP regulates branch morphogenesis in the kidney and lung, I reasoned that PCP may also regulate mammary gland branch morphogenesis. I first examined the expression of one of the core PCP proteins, Vangl2, in mammary gland development. Vangl2 was asymmetrically localized on the nipple side of the luminal cell membrane, suggesting PCP is indeed established in mammary gland ductal cells. Interestingly, when I analyzed Vangl2 in different stages of mammary gland development, I found that Vangl2 protein was differentially expressed in puberty and reproductive cycle stages. I next used in vivo genetic knockout and overexpression strategies to examine the loss-of-function and gain-of-function effects of PCP. The results showed that PCP loss-of-function stunted mammary gland development in puberty. On the contrary, PCP gain-of-function led to extra little branches and end buds. PCP loss-of-function also resulted in smaller alveoli in the reproductive cycle. However, interestingly, although Vangl2 expression was silent in the lactation stage and gradually appeared in the involution stage, neither Vangl2 overexpression in the lactation stage nor loss of Vangl2 in the involution stage led to morphological defects in the mammary gland. Collectively, I demonstrate that PCP signaling regulates mammary gland pubertal and reproductive development. After investigating mammary gland development, I studied the molecular mechanism of breast cancer progression. Now, with the increased risk, breast cancer is the most frequently diagnosed cancer, which seriously harms global health. Although present therapies are efficient for the treatment of early mammary tumors, there are still limitations in advanced breast cancer treatment. Thus, it is urgent to find new therapeutic targets and strategies, particularly for patients with advanced or metastatic breast cancer. Recently, androgen receptor (AR) signaling in cancer progression attracts increasing attention. Here, I found that Kindlin-2, a focal-adhesion-related protein, was crucial for Src-induced AR phosphorylation at the tyrosine 534 site. Then, phosphorylated AR is translocated to the cell nucleus, which facilitates target gene expression, and consequently regulates breast cancer cell proliferation and migration. On the contrary, RNA interference aimed at Kindlin-2 significantly reduced Src-induced AR Y534 phosphorylation and downstream signaling. In addition, unlike wild-type Kindlin-2, neither AR binding-deficient nor Src binding-deficient Kindlin-2 mutant rescued deficiency caused by loss of Kindlin-2. Further, genetic knockout Kindlin-2 in vivo led to reduced AR Y534 phosphorylation and inhibited cancer progression, which was consistent with our in vitro finding. Based on the results, I raised a model that Kindlin-2 served as a scaffold, simultaneously associating with AR and Src to mediate Src-induced AR Y534 phosphorylation.
关键词	Mammary Gland Development Breast Cancer Planar Cell Polarity Kindlin-2 Androgen Receptor
语种	英语
培养类别	联合培养
入学年份	2018
学位授予年份	2023-07
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专题	生命科学学院_生物系
推荐引用方式 GB/T 7714	Ma LY. MOLECULAR MECHANISM OF MAMMARY GLAND DEVELOPMENT AND BREAST CANCER PROGRESSION[D]. 香港. 香港大学,2022.

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